Therapeutic misadventures with acetaminophen: Hepatoxicity after multiple doses in children,☆☆,,★★

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Abstract

We compiled reports of acetaminophen hepatotoxicity after multiple overdoses from published cases, cases reported to the Food and Drug Administration, and cases from Children's Hospital Medical Center, Cincinnati, Ohio. Forty-seven children (age range, 5 weeks to 10 years) received 60 to 420 mg/kg/day for 1 to 42 days; 52% had received adult preparations of acetaminophen. The mean peak serum aspartate aminotransferase level was 10,225 IU/L (n = 45), and the mean serum alanine aminotransferase level was 7355 IU/L (n = 31), which were significantly higher (both p < 0.001) than the mean serum aspartate aminotransferase level of 3500 IU/L and alanine aminotransferase level of 3098 IU/L found in children (n = 12) with non-acetaminophen-associated hepatic failure. Serum acetaminophen levels for which an estimate of time from last dose could be calculated were available for 30 patients, of which 22 levels were greater than the toxic range described for acute ingestion. Twenty-four of 43 patients (55%) died, with an additional three surviving after orthotopic liver transplantation. Parents should be advised about the potential hepatotoxicity of acetaminophen when given to ill children in doses exceeding weight-based recommendations. (J Pediatr 1998;132:22-7)

Section snippets

Data Collection

Three cases derived from patients hospitalized at the Children's Hospital between 1979 and 1995 were identified by ICD9-CM chart search for fulminant hepatic failure and through direct involvement by members of the Division of Pediatric Gastroenterology and Nutrition. In each case the medical record was reviewed by one of the authors (JEH). MEDLINE and the International Pharmaceutical Abstracts database were searched during the summer of 1995 to identify published cases of acetaminophen-related

Results

Forty-seven patients fulfilled criteria for the diagnosis of acetaminophen hepatotoxicity associated with multiple dosing. Twenty-eight cases had previously been reported as case reports or in AAPCC abstracts.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 Thirteen cases were excluded because they were reports of single large ingestions, and 19 cases were excluded because there were insufficient data to conclusively determine that acetaminophen was the

Discussion

This report provides a compilation of all previously well-documented cases of repeated accidental overdosage of acetaminophen in children. It also includes 20 previously unreported cases and therefore represents the single largest collection of cases of liver injury associated with long-term acetaminophen administration in children. The 47 cases described in this report add to the eight nonoverlapping cases reported by Rivera-Penera et al.4 This total of 55 cases is small compared with the

Acknowledgements

We thank Andrea Smith, Patricia Calvin, and Catherine McGraw for assistance in the preparation of the manuscript, table, and figures. We also thank Drs. William F. Balistreri and John C. Bucuvalas for their helpful suggestions regarding the content of the manuscript. Ms. Barbacci's contribution to this report was originally done in connection with gathering literature for litigation involving acetaminophen-related injuries to children. Dr. Heubi has served as an expert witness in

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    From the Division of Pediatric Gastroenterology and Nutrition, Children's Hospital Medical Center, Cincinnati, Ohio; the Department of Medicine, George Washington University, Washington, D.C.; and Armed Forces Institute of Pathology, Washington, D.C.

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    Supported in part by U.S. Public Health Service grant no. M01 RR-08084 from the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.

    Reprint requests: James E. Heubi, MD, Clinical Research Center, Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039.

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